Methods for enhancing the potency of the immune checkpoint inhibitors

Abstract

The present invention relates to methods for enhancing the potency of the immune checkpoint inhibitors. In particular, the present invention relates to a method for enhancing the potency of an immune checkpoint inhibitor administered to a subject as part of a treatment regimen, the method comprising administering a pharmaceutically effective amount of a SK1 inhibitor to a subject in combination with the immune checkpoint inhibitor.

Description

FIELD OF THE INVENTION[0001]The present invention relates to methods for enhancing the potency of the immune checkpoint inhibitors.BACKGROUND OF THE INVENTION[0002]The ability of the immune system to detect and eliminate cancer was first proposed over 100 years ago. Since then, T cells reactive against tumor-associated antigens have been detected in the blood of patients with many different types of cancers, suggesting a role for the immune system in fighting cancer. However, tumors can escape host immunity by manipulating the tumor microenvironment and driving immunosuppression, meaning that patients cannot mount a potent enough immune response to fully eliminate cancer cells. The goal of immunotherapy is to restore or augment antitumor immune responses. An increased understanding of tumor immunology has led to the identification of novel targets for new immune-based approaches, including a group of cell-surface molecules known as immune checkpoint proteins. In particular, monoclon...

AI Technical Summary

Benefits of technology

[0005]The inventors demonstrated that interfering with sphingolipid metabolism efficiently impairs tumor progression in pre-clinical melanoma model and enhances anti-tumor immune response obtained with the immune checkpoint inhibitor. In particular, the inventors observed that SK1 downregulation enhances proliferation and activation of CD8+ T cells within the tumors. Of great interest is the finding that SK1 knockdown in melanoma enhances the expression of CTLA-4 and PD-1 on CD8+ TIL, which are both up-regulated upon T cell activation and exert potent negative feedback loop on T cell activation. The latter observation highlights for the first time that melanoma SK1 impairs CD8+ T cell-dependent immune response. However, the upregulation of both PD-1 and CTLA-4 on CD8+ T cells is likely involved in the melanoma immune escape following SK1 knockdown observed at latter time points. Thus, targeting melanoma SK1 is unlikely sufficient to trigger total tumor regression. Collectively, the data prompted the inventors to investigate the combination of SK1 inhibition with the inhibition of immune checkpoints and demonstrate that said combination provides synergistic anti-cancer immune responses.

[0008]A further object of the present invention relates to a method for enhancing the potency of an immune checkpoint inhibitor administered to a subject as part of a treatment regimen, the method comprising administering to the subject a pharmaceutically effective amount of a SK1 inhibitor in combination with the immune checkpoint inhibitor.

[0011]Thus the expression “enhancing the potency of an immune checkpoint” refers to the ability of the SK1 inhibitor to increase the ability of the immune checkpoint inhibitor to enhance the proliferation, migration, persistence and / or cytoxic activity of CD8+ T cells.

[0017]Accordingly a further object of the present invention relates to a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective combination of an immune checkpoint inhibitor with a SK1 inhibitor, wherein administration of the combination results in enhanced therapeutic efficacy relative to the administration of the immune checkpoint inhibitor alone.

Problems solved by technology

However, tumors can escape host immunity by manipulating the tumor microenvironment and driving immunosuppression, meaning that patients cannot mount a potent enough immune response to fully eliminate cancer cells.

Despite promising results, about 40% of patients do not display therapeutic response and a significant proportion of responders experience tumor relapse in the 2 years following treatment induction.

Moreover, recent clinical trials combining BRAF and checkpoint inhibitors have shown high liver toxicity for patients with BRAF-mutated melanoma.

However, the prior art does not suggest SK1 inhibition could enhance the potency of the immune checkpoint inhibitors.

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